BLOOD-BRAIN DISPOSITION AND ANTINOCICEPTIVE EFFECTS OF [D-PENICILLAMINE(2,5)]ENKEPHALIN IN THE MOUSE

Although intravenous administration of [D-penicillamine(2,5)]-enkephal in (DPDPE) produces significant antinociception in rodents, the durati on of antinociception is short (similar to 15 min). The present study was conducted to test the hypothesis that duration of antinociception for DPDPE is determined by both systemic and regional disposition (i.e ., blood-brain translocation), and that the magnitude of antinocicepti on is related more closely to concentrations in brain tissue than in b lood. Systemic disposition was examined after i.v. administration of D PDPE (10-100 mg/kg) to male CD-I mice. The relationship between antino ciception and concentration in blood and brain tissue was assessed by determining antinociception 10 min after administration of DPDPE (10-1 00 mg/kg); effect versus brain tissue concentration data were fit with pharmacodynamic models to recover EC50 estimates. In addition, the ti me course oi antinociception, as well as blood and brain tissue concen trations, were examined after an i.v. bolus dose (40 mg/kg) of DPDPE. The systemic disposition of DPDPE was nonlinear; both clearance and vo lume of distribution were dose-dependent. Antinociception increased pr oportionately with increasing concentrations of DPDPE in blood or brai n tissue, with an EC50 of 1.42 +/- 0.06 mu g/g expressed as brain tiss ue concentration. However, the brain-to-blood concentration ratio also increased with increasing dose, suggestive of saturable translocation of DPDPE across the blood-brain barrier. Antinociception appeared rap idly (within 5 min) and dissipated within similar to 15 min after a 40 mg/kg i.v. dose, These results suggest that rapid elimination from bl ood and active efflux from brain limit the duration of action of DPDPE .